JPH0615556B2 - 4-Carbamoyl-1-β-D-ribofuranosyl-imidazolium-5-oleate anhydrous crystal - Google Patents
4-Carbamoyl-1-β-D-ribofuranosyl-imidazolium-5-oleate anhydrous crystalInfo
- Publication number
- JPH0615556B2 JPH0615556B2 JP1291078A JP29107889A JPH0615556B2 JP H0615556 B2 JPH0615556 B2 JP H0615556B2 JP 1291078 A JP1291078 A JP 1291078A JP 29107889 A JP29107889 A JP 29107889A JP H0615556 B2 JPH0615556 B2 JP H0615556B2
- Authority
- JP
- Japan
- Prior art keywords
- mizoribine
- crystal
- crystals
- anhydrous
- monohydrate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/052—Imidazole radicals
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S435/00—Chemistry: molecular biology and microbiology
- Y10S435/8215—Microorganisms
- Y10S435/911—Microorganisms using fungi
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】 〔産業上の利用分野〕 本発明は熱及び水分に対し優れた安定性を有し、かつ製
造において簡便に得られる４−カルバモイル−１−β−
Ｄ−リボフラノシル−イミダゾリウム−５−オレイト
（４−carbamoyl−１−β−Ｄ−ribofuranosyl imidazo
lium−５−olate）の新規な無水結晶に関する。DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention has 4-carbamoyl-1-β-, which has excellent stability against heat and moisture and can be easily obtained in production.
D-ribofuranosyl-imidazolium-5-oleate (4-carbamoyl-1-β-D-ribofuranosyl imidazo
lium-5-olate).
４−カルバモイル−１−β−Ｄ−リボフラノシル−イミ
ダゾリウム−５−オレイト（以下「ミゾリビン」と略称
する）はオイペニシリウム・ブレフェルディアナム(Eup
enicillium brefeldianum)Ｍ−２１６６株(FERM P-110
4)の培養液より発見された核酸関連物質であって、水に
昜溶で、２００℃付近で褐色発泡分解する弱酸性物質で
ある。ミゾリビンの製造法としては種々の方法が知ら
れ、一水和物として得られている〔J.Antibiotics.,27,
(10),775(1974)、Chem.Pharm.Bull.,23,245(1975)、特開
昭48-56894号公報、特開昭51-1693号公報、特開昭50-121
275号公報、特開昭50-121276号公報等〕。4-carbamoyl-1-β-D-ribofuranosyl-imidazolium-5-oleate (hereinafter abbreviated as “mizoribine”) is Eupenicillium brefeldianum (Eup)
enicillium brefeldianum) M-2166 strain (FERM P-110
A nucleic acid-related substance found in the culture solution of 4), which is a weakly acidic substance that dissolves in water and undergoes brown foaming decomposition at around 200 ° C. Various methods are known as a method for producing mizoribine, and they are obtained as a monohydrate [J. Antibiotics., 27,
(10), 775 (1974), Chem.Pharm.Bull., 23,245 (1975), JP-A-48-56894, JP-A-51-1693, JP-A-50-121.
275, JP-A-50-121276, etc.].
ミゾリデンは優れた免疫抑制作用を有し、ブレディニン
錠（登録商標；東洋醸造(株)）という商品名で、腎移植
における拒絶反応の抑制などを目的として広く臨床適用
されている。その用法・用量は通常体重１kg当たり、初
期量としてミゾリビン２〜３mg相当量、維持量として１
〜２mg相当量を１日量として経口投与するものである。Mizolidene has an excellent immunosuppressive action and is widely clinically applied under the trade name of Bredinin tablet (registered trademark; Toyo Shuzo Co., Ltd.) for the purpose of suppressing rejection in renal transplantation. The dosage / usage is usually 2 to 3 mg of mizoribine as the initial amount and 1 as the maintenance amount per 1 kg of body weight.
It is orally administered in a daily dose equivalent to 2 mg.
ところでミゾリビンの結晶としては、一水和物の結晶及
び無水結晶の２種類が知られている。一水和物の結晶
は、約６〜７重量％（以下、単に％で示す）（理論量6.
5％）の水分を含有し、複光束式（分散型）赤外分光光
度計によるその赤外吸収スペクトル（KBr法、以下同
じ）は3420、3130、2925、2770、1625、1540、1445、1300、126
0、1195、1100、1080、1055、1030、980、873、829、770、740、72
5、560cm-1付近〔J.Antibiotics.,27,(10),775(1974)、
特開昭48-56894号公報〕の各波長に吸収ピークを有す
る。By the way, two types of crystals of mizoribine are known, a monohydrate crystal and an anhydrous crystal. The crystals of monohydrate are about 6 to 7% by weight (hereinafter, simply expressed as%) (theoretical amount: 6.
The infrared absorption spectrum (KBr method, the same applies hereinafter) of a double-beam (dispersion) infrared spectrophotometer containing 3%) is 3420, 3130, 2925, 2770, 1625, 1540, 1445, 1300. , 126
0, 1195, 1100, 1080, 1055, 1030, 980, 873, 829, 770, 740, 72
5, 560 cm -1 (J. Antibiotics., 27, (10), 775 (1974),
JP-A-48-56894] has an absorption peak at each wavelength.
またフェーリエ変換式（干渉型）赤外分光光度計（誤差
範囲は±２cm-1）による一水和物の赤外吸収スペクトル
は3422、3323、3122、2947、2913、1689、1617、1548、1444、138
5、1297、1208、1154、1140、1107、1080、1062、1035、982、946、
874、843、824、779、746、724、679、627、567、482cm-1付近の
各波長に吸収ピークを有する（第３図）。一方、従来の
無水結晶（以下、「無水結晶Ａ」と称する）は約0.5%以
下の水分を含有し、干渉型赤外分光光度計による赤外吸
収スペクトルは、3469、3348、3292、3139、3018、2943、287
4、1654、1621、1593、1542、1438、1371、1347、1328、1311、128
2、1249、1213、1188、1130、1103、1058、1027、978、947、865、8
27、777、768、749、668、645、630、603、571、501cm-1付近の各
波長に吸収ピークを有するものである（第２図）。In addition, the infrared absorption spectrum of monohydrate using a Ferrier transform (interferometric) infrared spectrophotometer (with an error range of ± 2 cm -1 ) is 3422, 3323, 3122, 2947, 2913, 1689, 1617, 1548, 1444. , 138
5, 1297, 1208, 1154, 1140, 1107, 1080, 1062, 1035, 982, 946,
It has absorption peaks at wavelengths around 874, 843, 824, 779, 746, 724, 679, 627, 567 and 482 cm -1 (Fig. 3). On the other hand, a conventional anhydrous crystal (hereinafter referred to as “anhydrous crystal A”) contains about 0.5% or less of water, and the infrared absorption spectrum by an interference infrared spectrophotometer is 3469, 3348, 3292, 3139, 3018, 2943, 287
4, 1654, 1621, 1593, 1542, 1438, 1371, 1347, 1328, 1311, 128
2, 1249, 1213, 1188, 1130, 1103, 1058, 1027, 978, 947, 865, 8
It has absorption peaks at wavelengths around 27, 777, 768, 749, 668, 645, 630, 603, 571 and 501 cm -1 (Fig. 2).
しかし、通常の培養法又は化学合成法における単離手段
で単離される結晶であるミゾリビン一水和物の結晶が、
高温及び高湿度条件において不安定であり、例えばミゾ
リビン一水和物結晶をバイアル瓶に入れ、密封した後６
５℃の条件に放置すると２４時間後には暗緑色に着色
し、かつ固化してしまうという欠点を有する。また例え
ばミゾリビン一水和物結晶を五酸化リン、４０℃、４８
時間真空乾燥して水分を除去し、これをバイアル瓶に入
れて開封状態で２０℃、９５％相対湿度の条件下に放置
したところ２４時間で理論水分量である含水率6.5%程度
に戻り、さらに７日間保存することにより淡黄緑色の着
色を生じた不安定なものであった。従ってこのミゾリビ
ン一水和物結晶は、製剤化においても安定性に問題があ
り、市販されていない。However, a crystal of mizoribine monohydrate, which is a crystal isolated by an isolation means in an ordinary culture method or a chemical synthesis method,
It is unstable in high temperature and high humidity conditions, for example, mizoribine monohydrate crystals are placed in a vial, and after sealing, 6
When left at 5 ° C., it has a defect that it is colored dark green and solidifies after 24 hours. Also, for example, mizoribine monohydrate crystals are treated with phosphorus pentoxide at 40 ° C.
After vacuum drying for a period of time to remove water, the product was placed in a vial and left in an open state under conditions of 20 ° C and 95% relative humidity. After 24 hours, it returned to a theoretical water content of about 6.5%, When it was stored for another 7 days, it was unstable and had a pale yellow-green coloration. Therefore, this mizoribine monohydrate crystal has a problem in stability in formulation and is not commercially available.
一方、無水結晶Ａは市販のブレディニン錠製剤に配合さ
れているものであり、一水和物結晶に比較すれば安定で
はあるものの、例えばその製造において無水結晶Ａの少
量を種結晶として用い、一水和物のメタノール媒体から
製造される煩雑な工程を伴って得られ、またこの無水結
晶Ａは、その製造時に、製造装置、器具の表面に析出固
着し易く、その洗浄除去が著しく困難であり、かつメタ
ノールを媒体として得られるため、用いたメタノールを
充分に除去する必要があった。On the other hand, the anhydrous crystal A is contained in a commercially available tablet preparation of Bredinin and is more stable than the monohydrate crystal, but for example, a small amount of the anhydrous crystal A was used as a seed crystal in the production thereof. It is obtained by a complicated process of producing a hydrate from a methanol medium, and the anhydrous crystal A is easily deposited and fixed on the surface of a production apparatus or equipment during its production, and its removal by washing is extremely difficult. Further, since methanol can be obtained as a medium, it is necessary to sufficiently remove the used methanol.
このような状況下、ミゾリビンの無水結晶について、何
ら多形性の報告は知られていないものであった。Under such circumstances, no report of polymorphism was found in the anhydrous crystals of mizoribine.
かかる実情において本発明者らは、前記問題点を解決す
べく種々検討したところ、全く意外にもミゾリビンには
従来の一水和物及び無水結晶Ａ以外の新しい結晶が存在
し、その新しい結晶は熱及び湿気に対し極めて安定で、
安全なエタノールを媒体として容易に製造でき、しかも
その製造時において装置・器具の表面への固着を生じな
いことから洗浄が極めて容易であるなどの製造上の利点
があることを見出し本発明を完成した。Under such circumstances, the present inventors have made various investigations to solve the above-mentioned problems, and surprisingly, there are new crystals other than conventional monohydrate and anhydrous crystal A in mizoribine, and the new crystals are Extremely stable against heat and moisture,
We have completed the present invention by discovering that there are manufacturing advantages such as safe ethanol that can be easily produced as a medium, and that it is extremely easy to wash because it does not stick to the surface of the device / appliance during the production. did.
すなわち、本発明は次の性質を有することを特徴とする
４−カルバモイル−１−β−Ｄ−リボフラノシル−イミ
ダゾリウム−５−オレイト無水結晶（以下、本発明結晶
と称する）を提供するものである。That is, the present invention provides 4-carbamoyl-1-β-D-ribofuranosyl-imidazolium-5-oleate anhydrous crystal (hereinafter, referred to as the crystal of the present invention) characterized by having the following properties. .
(1)水分量 0.5%以下（カールフィッシャー法） (2)赤外吸収スペクトル（干渉型赤外分光光度計によ
る） 3580、1852、1630、1575、1554cm-1付近（誤差範囲は±２cm
-1）に吸収ピークを有する。(1) Water content 0.5% or less (Karl Fischer method) (2) Infrared absorption spectrum (by interferometric infrared spectrophotometer) 3580, 1852, 1630, 1575, 1554 cm -1 (within ± 2 cm error range)
-1 ) has an absorption peak.
本発明結晶は、例えば、ミゾリビン一水和物結晶をエタ
ノールに添加し、室温以上ないしミゾリビンを分解しな
い温度条件下、攪拌し、次いで得られた溶液を冷却し、
析出した結晶を乾燥することにより製造される。Crystals of the present invention, for example, mizoribine monohydrate crystals are added to ethanol, stirred at room temperature or higher temperature conditions that do not decompose mizoribine, then stirred, then the resulting solution is cooled,
It is produced by drying the precipitated crystals.
原料として使用されるミゾリビン一水和物結晶は、上記
の培養法又は化学合成法に関する文献に記載の方法によ
って製造することができる。このミゾリビン一水和物結
晶は、約６〜７％（理論量6.5%）の水分を含有し、第３
図に示す赤外吸収スペクトルを示す。このミゾリビン一
水和物結晶は、溶媒に添加するにあたり適宜粉砕して用
いるのが好ましい。The crystals of mizoribine monohydrate used as a raw material can be produced by the method described in the literature relating to the above-mentioned culture method or chemical synthesis method. The crystals of mizoribine monohydrate contain about 6-7% (theoretical amount 6.5%) of water,
The infrared absorption spectrum shown in the figure is shown. The mizoribine monohydrate crystals are preferably crushed and used as appropriate before being added to the solvent.
また、本発明の無水結晶を得るに当って用いられる媒体
であるエタノールは含水率５０％以下、好ましくは含水
率２５％以下、特に好適には２０％以下の含水のエタノ
ールである。またこのようなエタノールを用いるにあた
っては、溶媒の使用量、下記の加熱条件等の要件を勘案
して適宜当該溶媒の含水率を決定すればよいが、通常ミ
ゾリビン一水和物１重量部当たり２５％ないし0.05％の
含水エタノール又は純度１００％エタノールの５重量部
以上、好ましくは１０重量部以上を使用すればよく、そ
の上限使用量は何ら限定されるものではないが、工業的
生産における効率を考慮して５０重量部まで、好ましく
は３０重量部までであればよい。Further, ethanol, which is a medium used for obtaining the anhydrous crystal of the present invention, is water-containing ethanol having a water content of 50% or less, preferably a water content of 25% or less, and particularly preferably 20% or less. When using such ethanol, the water content of the solvent may be appropriately determined in consideration of the amount of the solvent used, the heating conditions described below, and the like, but it is usually 25 per 1 part by weight of mizoribine monohydrate. % Or 0.05% hydrous ethanol or 100% pure ethanol may be used in an amount of 5 parts by weight or more, preferably 10 parts by weight or more. The upper limit of the amount used is not limited, but the efficiency in industrial production is not limited. Considering this, it may be up to 50 parts by weight, preferably up to 30 parts by weight.
これらのエタノールの溶媒にミゾリビン一水和物を添加
して本発明の無水結晶を得るには、室温以上ないしミゾ
リビンを分解しない温度条件にて適宜加熱してもよい
が、好ましくは５０℃ないし還流温度にて、例えば３０
分ないし５時間攪拌を行えばよい。In order to obtain the anhydrous crystal of the present invention by adding mizoribine monohydrate to a solvent of these ethanol, heating may be appropriately performed at room temperature or higher or under temperature conditions at which mizoribine is not decomposed, but preferably 50 ° C. or reflux. At temperature, eg 30
The stirring may be performed for 5 minutes to 5 hours.
得られた溶液を結晶が析出する温度、例えば１０℃以
下、好ましくは用いた溶媒が凍結しない冷却温度範囲、
特に好ましくは５℃〜０℃に冷却し、次いで析出した結
晶を乾燥させれば本発明の結晶が得られる。なお、本発
明結晶の乾燥法は特に限定されないが、減圧（真空）乾
燥法により例えば４０℃にて２０時間以上行えばよい。The temperature at which crystals are deposited in the obtained solution, for example, 10 ° C. or lower, preferably a cooling temperature range in which the solvent used does not freeze,
Particularly preferably, the crystals of the present invention are obtained by cooling to 5 ° C. to 0 ° C. and then drying the precipitated crystals. The method for drying the crystal of the present invention is not particularly limited, but may be carried out by a reduced pressure (vacuum) drying method at 40 ° C. for 20 hours or more.
かくして得られる本発明結晶は次の性質を有する。The crystals of the present invention thus obtained have the following properties.
(1)水分含量 0.5%以下、好ましくは0.3％以下（カールフィッシャー
法による） (2)赤外吸収スペクトル 3580、3397、3355、3192、3142、2901、2712、1852、1630、1575、
1554、1448、1360、1339、1320、1299、1280、1238、1204、1133、
1093、1047、1031、1011、993、941、895、878、858、806、769、71
3、667、638、610、550cm-1付近に吸収ピークを有する（第
１図：干渉型赤外分光光度計による）。(1) Water content 0.5% or less, preferably 0.3% or less (by Karl Fischer method) (2) Infrared absorption spectrum 3580, 3397, 3355, 3192, 3142, 2901, 2712, 1852, 1630, 1575,
1554, 1448, 1360, 1339, 1320, 1299, 1280, 1238, 1204, 1133,
1093, 1047, 1031, 1011, 993, 941, 895, 878, 858, 806, 769, 71
It has absorption peaks near 3, 667, 638, 610 and 550 cm -1 (Fig. 1: by interferometric infrared spectrophotometer).
これらの干渉型赤外分光光度計による吸収ピークのう
ち、ミゾリビン一水和物（第３図）及びミゾリビン無水
結晶Ａ（第２図）のいずれにもない吸収ピークは次の通
りである。Among the absorption peaks obtained by these interferometric infrared spectrophotometers, the following absorption peaks are not found in both mizoribine monohydrate (FIG. 3) and anhydrous mizoribine crystal A (FIG. 2).
3580、1852、1630、1575、1554cm-1付近。Near 3580, 1852, 1630, 1575, 1554 cm -1 .
(3)安定性 熱安定性 バイアル瓶に入れ、密封した後６５℃の条件に２週間放
置しても着色等の外観変化は全く認められない。(3) Stability Heat stability No change in appearance such as coloration is observed even when placed in a vial, sealed, and allowed to stand at 65 ° C for 2 weeks.
高湿度条件下安定性 バイアル瓶に入れて開封状態で２０℃、９５％相対湿度
の条件下に２週間放置しても、ほとんど吸湿することな
く、安定。Stability under high humidity conditions Stable with almost no moisture absorption when placed in a vial and left open for 2 weeks at 20 ° C and 95% relative humidity.
(4)結晶形状 偏光顕微鏡による観察で針状。(4) Crystal shape Needle-like when observed with a polarizing microscope.
(5)洗浄条件 ミゾリビン無水結晶Ａに比べて本発明の無水結晶は、製
造装置・器具への固着成分の洗浄が容易である。(5) Washing conditions Compared with anhydrous crystals of mizoribine, the anhydrous crystals of the present invention make it easier to wash the components adhered to the manufacturing apparatus / apparatus.
上記の如く、本発明結晶は、熱及び高湿度条件下におい
て極めて安定で、安全なエタノール媒体を用いることに
より簡便に得られ、しかも製造装置・器具への固着成分
の洗浄が容易であるため、これを用いれば何ら特別の技
術を要することなく、経口投与用製剤を調製することが
できる。例えば、賦形剤として無水乳糖、結晶セルロー
ス、デキストラン、スターチなど、結合剤としてカルボ
キシメチルセルロースナトリウム、メチルセルロース、
エチルセルロースなど、崩壊剤としてはカルボキシメチ
ルセルロースカルシウム、炭酸カルシウム、メチルセル
ロースなど、滑沢剤としてステアリン酸、ステアリン酸
マグネシウム、タルクなどを適宜選択組合せ、常法によ
り錠剤、カプセル剤などの製剤とすることができる。As described above, the crystal of the present invention is extremely stable under the conditions of heat and high humidity, and can be easily obtained by using a safe ethanol medium, and moreover, since the adhered component to the production apparatus / equipment can be easily washed, If this is used, a preparation for oral administration can be prepared without requiring any special technique. For example, anhydrous lactose as an excipient, crystalline cellulose, dextran, starch, etc., sodium carboxymethyl cellulose as a binder, methyl cellulose,
As a disintegrating agent such as ethyl cellulose, carboxymethyl cellulose calcium, calcium carbonate, methyl cellulose and the like, and as a lubricant, stearic acid, magnesium stearate, talc and the like are appropriately selected and combined, and tablets, capsules and the like can be prepared by a conventional method. .
次いで実施例及び試験例を挙げて本発明を具合的に説明
するが、本発明は何らこれらによって限定されるもので
はない。Next, the present invention will be described in detail with reference to Examples and Test Examples, but the present invention is not limited thereto.
比較例１ ミゾリビン一水和物２０ｇに水１５mlを加え、加温して
溶解し、放冷後、５℃で一晩放置し、析出した結晶を濾
取し、４０℃一晩真空乾燥してミゾリビン一水和物結晶
18.7gを得た。次いでこのミゾリビン一水和物結晶１５
ｇに水１５mlを加え、加温して溶解し、これに９０mlの
アセトンを加え、５℃に冷却して一晩放置し、析出した
結晶を濾取し、冷アセトン１０mlで洗浄し、４０℃で一
晩真空乾燥して精製ミゾリビン一水和物結晶13.4gを得
た。本品の干渉型赤外吸収スペクトル（KBr法）は第３
図に示す通りで、また本品の偏光顕微鏡（倍率２００
倍）による結晶形状は第４図（図中、１cmは１０μｍを
意味する）に示すものであった。Comparative Example 1 20 ml of mizoribine monohydrate was added with 15 ml of water, dissolved by heating, allowed to cool, and allowed to stand at 5 ° C overnight, and the precipitated crystals were collected by filtration and vacuum dried at 40 ° C overnight. Mizoribine monohydrate crystal
18.7g was obtained. Then, this mizoribine monohydrate crystal 15
To 15 g of water, 15 ml of water was added and dissolved by heating, 90 ml of acetone was added thereto, and the mixture was cooled to 5 ° C and allowed to stand overnight. The precipitated crystals were collected by filtration, washed with 10 ml of cold acetone, and 40 ° C. After vacuum drying overnight, 13.4 g of purified mizoribine monohydrate crystals were obtained. The interference infrared absorption spectrum (KBr method) of this product is the third
As shown in the figure, and using a polarizing microscope (magnification of 200
The crystal shape obtained by doubling was that shown in FIG. 4 (in the figure, 1 cm means 10 μm).
比較例２ 種結晶としてミゾリビン無水結晶Ａ0.5gを用い、これと
上記比較例１と同様にして得られたミゾリビン一水和物
1.5gとをメタノール２０mlに懸濁した。次いでこれを６
８℃まで攪拌しながら加温し、そのまま３時間攪拌し
た。その後攪拌をとめ、氷水で５℃になるまで冷却し、
析出した結晶を濾取した。得られた結晶を冷メタノール
で洗浄後、室温で一晩、４０℃で２４時間減圧乾燥して
1.86gの結晶を得た。本品の干渉型赤外分光光度計によ
る赤外吸収スペクトルは第２図に示す通りであり、その
含水率（カーンフィッシャー法）は0.12％であり、ミゾ
リビン無水結晶Ａであった。Comparative Example 2 Mizoribine anhydrous crystal A 0.5 g was used as a seed crystal and mizoribine monohydrate obtained in the same manner as in Comparative Example 1 above.
1.5 g and were suspended in 20 ml of methanol. Then this 6
The mixture was heated to 8 ° C. with stirring and was stirred for 3 hours as it was. After that, stop stirring, cool with ice water to 5 ° C,
The precipitated crystals were collected by filtration. The crystals obtained were washed with cold methanol and dried under reduced pressure at room temperature overnight and 40 ° C. for 24 hours.
1.86 g of crystals were obtained. The infrared absorption spectrum of this product by an interference infrared spectrophotometer is as shown in FIG. 2, its water content (Kahn-Fisher method) was 0.12%, and it was anhydrous mizoribine crystal A.
実施例１ 比較例１で得た精製ミゾリビン一水和物結晶5.0gを、無
水エタノール５０ml に懸濁し、攪拌しながら沸騰水浴
中で６０分間還流させた。その後、氷水中で６０分間冷
却し、析出した結晶を４０℃、一晩真空乾燥してミゾリ
ビン無水物結晶4.61g（水分量0.11％）を得た。本品の
干渉型赤外吸収スペクトル（KBr法）は第１図に示す通
りで、また本品の偏光顕微鏡（倍率２００倍）による結
晶形状は第５図（図中、１cmは１０μｍを意味する）に
示すものであった。Example 1 5.0 g of purified mizoribine monohydrate crystals obtained in Comparative Example 1 was suspended in 50 ml of absolute ethanol and refluxed for 60 minutes in a boiling water bath with stirring. Then, it was cooled in ice water for 60 minutes, and the precipitated crystal was vacuum dried at 40 ° C. overnight to obtain 4.61 g of anhydrous mizoribine crystal (water content 0.11%). The interference infrared absorption spectrum (KBr method) of this product is as shown in FIG. 1, and the crystal shape of this product by a polarizing microscope (magnification: 200 times) is shown in FIG. 5 (1 cm means 10 μm in the figure). ).
実施例２〜１１ ミゾリビン一水和物結晶（原料）の使用量、溶媒及
び攪拌条件を変化させる以外は、実施例１と同様にし
て本発明ミゾリビン無水結晶を得た。その条件、収量及
び水分量を第１表に示す。Examples 2 to 11 An anhydrous mizoribine crystal of the present invention was obtained in the same manner as in Example 1 except that the amount of the mizoribine monohydrate crystal (raw material) used, the solvent and the stirring conditions were changed. The conditions, yield and water content are shown in Table 1.
試験例１（熱安定性試験） 本発明ミゾリビン無水結晶0.5gを３ml容のバイアル瓶に
入れ、密封した後６５℃の条件下に放置し、２４時間毎
に外観変化を観察した。 Test Example 1 (Thermal Stability Test) 0.5 g of anhydrous crystals of mizoribine of the present invention were placed in a 3 ml vial, sealed, and allowed to stand at 65 ° C., and changes in appearance were observed every 24 hours.
その結果、ミゾリビン一水和物結晶は２４時間で既に暗
緑色に着色し、固化した。これに対し、本発明結晶は、
いずれも２週間後でも全く外観に変化はみられなかっ
た。As a result, the crystals of mizoribine monohydrate were already dark green in 24 hours and solidified. On the other hand, the crystal of the present invention is
No change in appearance was observed at all even after 2 weeks.
試験例２（高湿度条件下での安定性試験） 本発明ミゾリビン無水結晶0.3gを３ml容のバイアル瓶に
入れ、開封状態で、２０℃、９５％相対湿度の条件下に
放置し、吸湿増量及びカールフィッシャー水分の変化を
調べた。Test Example 2 (Stability Test under High Humidity Condition) 0.3 g of anhydrous crystals of mizoribine of the present invention was placed in a 3 ml vial and left in an opened state at 20 ° C. and 95% relative humidity to increase moisture absorption. And the change of Karl Fischer water content was investigated.
その結果、ミゾリビン一水和物の乾燥品（五酸化リン存
在下、４０℃、４８時間真空乾燥、水分2.4％まで乾
燥）は、２４時間で約５％の増量を認め、水分量は約6.
5％になった。これに対し、本発明結晶は、いずれも２
週間後でもほとんど増量せず、水分量もほとんど変化し
なかった。As a result, the dry product of mizoribine monohydrate (in the presence of phosphorus pentoxide, vacuum dried at 40 ° C. for 48 hours, dried to 2.4% water content) showed an increase of about 5% in 24 hours, and the water content was about 6%. .
It became 5%. On the other hand, the crystals of the present invention are all 2
Even after a week, the amount of water was hardly increased and the amount of water was hardly changed.
試験例２（洗浄試験） 比較例１で得た精製ミゾリビン一水和物5.0gを無水エタ
ノール（エタノール純度99.5％）５０mlに懸濁し、攪拌
しながら水浴中で７０℃に保持し、その後氷水中で冷却
して本発明のミゾリビン無水結晶4.36g（水分0.12％）
を得た。Test Example 2 (Washing Test) 5.0 g of the purified mizoribine monohydrate obtained in Comparative Example 1 was suspended in 50 ml of absolute ethanol (ethanol purity 99.5%), and the suspension was maintained at 70 ° C. in a water bath while stirring, and then in ice water. Anhydrous mizoribine crystals of the present invention cooled by 4.36 g (water content 0.12%)
Got
また対照として、精製ミゾリビン一水和物4.0gとミゾリ
ビン無水結晶Ａの種結晶１ｇを無水メタノール（メタノ
ール純度99.6％）５０mlに懸濁し、攪拌しながら水浴中
で６５℃に保持し、氷水中で冷却してミゾリビン無水結
晶Ａ4.58g（水分0.21％）を得た。As a control, 4.0 g of purified mizoribine monohydrate and 1 g of seed crystals of anhydrous mizoribine crystal A were suspended in 50 ml of anhydrous methanol (methanol purity 99.6%), and the suspension was maintained at 65 ° C in a water bath while stirring, and then in ice water. After cooling, 4.58 g (water content 0.21%) of anhydrous crystals of mizoribine A were obtained.
次いで、この製造時の攪拌に用いたテフロン製攪拌羽根
を取り出し、２０ml容のビーカーに設置し、水洗による
各結晶の付着に対する洗浄状況を観察した。洗浄に当た
り、１回１０mlの水を分注器（PIPETMAN P-5000:GILS
ON社製）にて２回に分けて５mlづつ攪拌羽根に吹きかけ
て洗い、これを複数回繰り返し行い、それぞれの洗浄液
を回収し、次いで２７９nmにおける吸光度を測定した。
測定に当たり、ミゾリビンの水溶液における２７９nmで
の吸光度に関して５μｇ／mlの濃度の吸光度は0.28〜0.
29であることから、この吸光度以下になるまでの洗浄回
数を調べた。その結果、本発明のミゾリビン無水結晶の
場合は、洗浄８回目で吸光度0.512、９回目で吸光度0.1
07、１０回目で吸光度0.140、１１回目で吸光度0.083で
あり、１１回目の洗浄にて、用いた装置に付着したほぼ
すべての成分の洗浄をなし得た。これに対し、ミゾリビ
ン無水結晶Ａの場合は洗浄８回目の吸光度0.494、９回
目0.622、１０回目0.552、１１回目0.975、１２回目0.8
95、１３回目0.443、１４回目0.128、１５回目0.150で
あり、１５回目以上の洗浄を必要とするものであった。
従って本発明のミゾリビン無水結晶の場合は、製造装置
・器具の洗浄を容易になし得ることから、洗浄時間の短
縮が計れ、またその洗浄排液の少量化をなし得るもの
で、特に工場的スケールにおいて顕著な有用性を有す
る。Next, the Teflon stirring blade used for stirring during this manufacturing
Remove and place in a 20 ml beaker and rinse with water
The washing condition for the adhesion of each crystal was observed. Washed
10 ml of water is dispensed once (PIPETMAN P-5000: GILS
Sprayed on the stirring blade by 5 ml each in 2 times with ON)
Wash, repeat this several times, and wash each
Was collected and the absorbance at 279 nm was measured.
For measurement, at 279 nm in an aqueous solution of mizoribine
The absorbance at a concentration of 5 μg / ml is 0.28-0.
Since it is 29, the number of washing
I checked the number. As a result, the anhydrous crystals of mizoribine of the present invention
In the case of washing, the absorbance is 0.512 at the 8th wash and the absorbance is 0.1 at the 9th wash.
07, the absorbance is 0.140 at the 10th time, the absorbance is 0.083 at the 11th time
Yes, after the 11th washing, the
All the ingredients could be washed. In contrast, Mizoribi
In case of anhydrous crystal A, the absorbance at the 8th washing is 0.494, 9th
Eye 0.622, 10th 0.552, 11th 0.975, 12th 0.8
95th, 13th 0.443, 14th 0.128, 15th 0.150
Yes, the cleaning was required 15 times or more.
Therefore, in the case of the mizoribine anhydrous crystal of the present invention, the production apparatus
・ The cleaning time is short because the equipment can be easily cleaned.
Able to reduce contraction and reduce the amount of cleaning drainage
Have significant utility, especially on a factory scale
It
本発明のミゾリビン無水結晶は、熱及び高湿度条件にお
いて極めて優れた安定性を有し、何らメタノールを用い
ずに完全なエタノールを媒体として簡便に得られ、しか
も製造装置・器具への固着成分の洗浄が容易であり、効
率よく製造できる。さらにこのようにして得られた経口
投与用製剤の安定性も良好である。The anhydrous crystals of mizoribine of the present invention have extremely excellent stability under heat and high humidity conditions, can be easily obtained by using complete ethanol as a medium without using any methanol, and can be used as a component adhered to a manufacturing apparatus or instrument. Easy to wash and can be manufactured efficiently. Furthermore, the stability of the preparation for oral administration thus obtained is also good.
第１図は本発明ミゾリビン無水結晶の干渉型赤外分光光
度計による赤外吸収スペクトルを、第２図はミゾリビン
無水結晶Ａの干渉型赤外分光光度計による赤外吸収スペ
クトルを、第３図はミゾリビン一水和物の干渉型赤外分
光光度計による赤外吸収スペクトルを示す図面である。
第４図はミゾリビン一水和物の結晶構造を、第５図は本
発明ミゾリビン無水結晶の結晶構造（偏光顕微鏡，２０
０倍）を示す図面である。1 is an infrared absorption spectrum of anhydrous mizoribine crystal of the present invention measured by an interference infrared spectrophotometer, and FIG. 2 is an infrared absorption spectrum of anhydrous mizoribine crystal A of an interference infrared spectrophotometer. FIG. 3 is a drawing showing an infrared absorption spectrum of mizoribine monohydrate by an interference infrared spectrophotometer.
FIG. 4 shows the crystal structure of mizoribine monohydrate, and FIG. 5 shows the crystal structure of the anhydrous mizoribine crystal of the present invention (polarizing microscope, 20).
FIG.
Claims (1)
ルバモイル−１−β−Ｄ−リボフラノシル−イミダゾリ
ウム−５−オレイト無水結晶。 (1)水分含量 0.5重量％以下（カールフィッシャー法） (2)赤外吸収スペクトル 3580、1852、1630、1575及び1554cm-1付近に吸収ピーク
を有する。1. An anhydrous crystal of 4-carbamoyl-1-β-D-ribofuranosyl-imidazolium-5-oleate characterized by having the following properties. (1) Water content 0.5% by weight or less (Karl Fischer method) (2) Infrared absorption spectrum It has absorption peaks near 3580, 1852, 1630, 1575 and 1554 cm -1 .
Priority Applications (11)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1291078A JPH0615556B2 (en) | 1989-11-10 | 1989-11-10 | 4-Carbamoyl-1-β-D-ribofuranosyl-imidazolium-5-oleate anhydrous crystal |
| TW079108909A TW199164B (en) | 1989-11-10 | 1990-10-22 | |
| DE69025859T DE69025859T2 (en) | 1989-11-10 | 1990-10-22 | Anhydrous crystals of 4-carbamoyl-1-beta-D-ribofuranosyl-imidazolium-5-olate |
| AT90120255T ATE135364T1 (en) | 1989-11-10 | 1990-10-22 | ANHYDROUS CRYSTALS OF 4-CARBAMOYL-1-BETA-D-RIBOFURANOSYL-IMIDAZOLIUM-5-OLATE |
| EP90120255A EP0428879B1 (en) | 1989-11-10 | 1990-10-22 | Anhydrous crystal of 4-carbamoyl-1-beta-D-ribofuranosyl imidazolium-5-olate |
| CA002028416A CA2028416C (en) | 1989-11-10 | 1990-10-23 | Anhydrous crystal of 4-carbamoyl-1-.beta.-d-ribofuranosyl imidazolium-5-oleate |
| IE381790A IE62718B1 (en) | 1989-11-10 | 1990-10-24 | Anhydrous crystal of 4-carbomoyl-1-beta-d-ribofuranosyl imidazolium-5-olate |
| AU64939/90A AU631256B2 (en) | 1989-11-10 | 1990-10-24 | Anhydrous crystal of 4-carbamoyl-1-beta-d-ribofuranosyl imidazolium-5-oleate |
| KR1019900017154A KR960003618B1 (en) | 1989-11-10 | 1990-10-25 | Anhydrous crystal of 4-carbamoyl-1-beta-d-ribofuranosyl imidazolium-5-oleate |
| NZ235899A NZ235899A (en) | 1989-11-10 | 1990-10-30 | Anhydrous crystals of 4-carbamoyl-1-beta-d-ribofuranosyl imidazolium-5-olate and method of preparation |
| US08/231,011 US5442051A (en) | 1989-11-10 | 1994-04-21 | Anhydrous crystal of 4-carbamoyl-1-β-D-ribofuranosyl imidazolium-5-oleate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1291078A JPH0615556B2 (en) | 1989-11-10 | 1989-11-10 | 4-Carbamoyl-1-β-D-ribofuranosyl-imidazolium-5-oleate anhydrous crystal |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH03157393A JPH03157393A (en) | 1991-07-05 |
| JPH0615556B2 true JPH0615556B2 (en) | 1994-03-02 |
Family
ID=17764149
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1291078A Expired - Lifetime JPH0615556B2 (en) | 1989-11-10 | 1989-11-10 | 4-Carbamoyl-1-β-D-ribofuranosyl-imidazolium-5-oleate anhydrous crystal |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US5442051A (en) |
| EP (1) | EP0428879B1 (en) |
| JP (1) | JPH0615556B2 (en) |
| KR (1) | KR960003618B1 (en) |
| AT (1) | ATE135364T1 (en) |
| AU (1) | AU631256B2 (en) |
| CA (1) | CA2028416C (en) |
| DE (1) | DE69025859T2 (en) |
| IE (1) | IE62718B1 (en) |
| NZ (1) | NZ235899A (en) |
| TW (1) | TW199164B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI275394B (en) * | 2000-01-26 | 2007-03-11 | Asahi Chemical Corp | Mizoribin tablet improved with color tone change |
| JP4818994B2 (en) * | 2000-01-26 | 2011-11-16 | 旭化成ファーマ株式会社 | Mizoribine tablets with improved color change |
| JP2001300293A (en) * | 2000-04-25 | 2001-10-30 | Nipro Corp | Method for manufacturing inorganic or organic anhydride |
| CN103450300B (en) * | 2013-09-12 | 2015-10-28 | 华北制药集团新药研究开发有限责任公司 | A kind of method of purification of mizoribine |
| EP3822249A4 (en) | 2018-07-13 | 2022-04-13 | Kyowa Hakko Bio Co., Ltd. | Crystal of eucomic acid non-solvate and production method therefor |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3888843A (en) * | 1973-06-12 | 1975-06-10 | Toyo Jozo Kk | 4-carbamoyl-1-' -d-ribofuranosylimidazolium-5-olate |
| JPS5652038B2 (en) * | 1974-03-09 | 1981-12-09 | ||
| JPS511693A (en) * | 1974-06-21 | 1976-01-08 | Toyo Jozo Kk | 44 karubamoiru 11 beetaa dd ribofuranoshiiru imidazoriumu 55 oreitonoseizoho |
| JPS606634B2 (en) * | 1981-07-16 | 1985-02-19 | キッコーマン株式会社 | Method for producing cyclic-3',5'-guanylic acid |
| JPS5813394A (en) * | 1981-07-17 | 1983-01-25 | Ajinomoto Co Inc | Preparation of 1-beta-d-ribofuranosyl-4,5-substituted- imidazole |
| EP0427799B1 (en) * | 1989-01-24 | 1994-11-30 | Gensia, Inc. | Method and compounds for aica riboside delivery and for lowering blood glucose |
| IL99124A (en) * | 1990-08-10 | 1998-02-22 | Gensia Pharma | Substituted imidazole analogs of aica riboside |
-
1989
- 1989-11-10 JP JP1291078A patent/JPH0615556B2/en not_active Expired - Lifetime
-
1990
- 1990-10-22 AT AT90120255T patent/ATE135364T1/en not_active IP Right Cessation
- 1990-10-22 EP EP90120255A patent/EP0428879B1/en not_active Expired - Lifetime
- 1990-10-22 DE DE69025859T patent/DE69025859T2/en not_active Expired - Lifetime
- 1990-10-22 TW TW079108909A patent/TW199164B/zh active
- 1990-10-23 CA CA002028416A patent/CA2028416C/en not_active Expired - Lifetime
- 1990-10-24 AU AU64939/90A patent/AU631256B2/en not_active Expired
- 1990-10-24 IE IE381790A patent/IE62718B1/en not_active IP Right Cessation
- 1990-10-25 KR KR1019900017154A patent/KR960003618B1/en not_active IP Right Cessation
- 1990-10-30 NZ NZ235899A patent/NZ235899A/en unknown
-
1994
- 1994-04-21 US US08/231,011 patent/US5442051A/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| EP0428879A2 (en) | 1991-05-29 |
| KR960003618B1 (en) | 1996-03-20 |
| NZ235899A (en) | 1991-12-23 |
| IE62718B1 (en) | 1995-02-22 |
| TW199164B (en) | 1993-02-01 |
| CA2028416A1 (en) | 1991-05-11 |
| DE69025859T2 (en) | 1996-10-31 |
| JPH03157393A (en) | 1991-07-05 |
| KR910009723A (en) | 1991-06-28 |
| US5442051A (en) | 1995-08-15 |
| CA2028416C (en) | 1999-09-07 |
| AU6493990A (en) | 1991-05-16 |
| ATE135364T1 (en) | 1996-03-15 |
| EP0428879B1 (en) | 1996-03-13 |
| EP0428879A3 (en) | 1991-08-07 |
| IE903817A1 (en) | 1991-05-22 |
| DE69025859D1 (en) | 1996-04-18 |
| AU631256B2 (en) | 1992-11-19 |
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